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A study published in the journal Proceedings of the National Academy of Sciences (PNAS) by scientists at the UMass Medical School provides considerable insight into the mechanism of action of ataluren, a drug that has shown promise in treating patients with Duchene muscular dystrophy (DMD).

DMD is a degenerative disease that affects 20,000 children worldwide. Thirteen percent of cases are caused by a genetic mutation known as a nonsense mutation. In these cases, the mutation is a misplaced genetic “stop sign” that tells the cellular machinery to stop making the protein dystrophin before its production is complete.

“Our new data is scientifically important because ataluren restores activity to genes inactivated by nonsense mutations, and as a result, it has the potential to do so much for a large number of very complex genetic disorders,” said Allan Jacobson, PhD, the Gerald L. Haidak, MD, and Zelda S. Haidak professor of cell biology, and chair of microbiology & physiological systems. Ataluren (under the name Translarna) has been approved for the treatment of nonsense mutation DMD in the European Union since 2014.

Dr. Jacobson, who co-founded PTC Therapeutics, the company that developed ataluren, has been seeking to understand how the drug allows the ribosome, a cellular protein synthesis machine, to essentially skip over the stop signs and produce normal proteins. In the latest study, Jacobson and his UMMS team, and their research collaborators at the University of Alabama and PTC Therapeutics demonstrated that ataluren promotes insertion of specific transfer RNA (tRNA) molecules at premature stop signals in messenger RNA (mRNA), that the latter process yields functional proteins. They found that precise base-pairing interactions between tRNA and mRNA are critical to the mechanism.

“We are incredibly encouraged by our findings and are hopeful ataluren will have a broad impact on DMD patients, and other genetic diseases as well,” Jacobson said.